Mitochondria-specific drug release and reactive oxygen species burst induced by polyprodrug nanoreactors can enhance chemotherapy

Abstract

Cancer cells exhibit slightly elevated levels of reactive oxygen species (ROS) compared with normal cells, and approximately 90% of intracellular ROS is produced in mitochondria. In situ mitochondrial ROS amplification is a promising strategy to enhance cancer therapy. Here we report cancer cell and mitochondria dual-targeting polyprodrug nanoreactors (DT-PNs) covalently tethered with a high content of repeating camptothecin (CPT) units, which release initial free CPT in the presence of endogenous mitochondrial ROS (mtROS). The in situ released CPT acts as a cellular respiration inhibitor, inducing mtROS upregulation, thus achieving subsequent self-circulation of CPT release and mtROS burst. This mtROS amplification endows long-term high oxidative stress to induce cancer cell apoptosis. This current strategy of endogenously activated mtROS amplification for enhanced chemodynamic therapy overcomes the short lifespan and action range of ROS, avoids the penetration limitation of exogenous light in photodynamic therapy, and is promising for theranostics.

Facile Nanolization Strategy for TherapeuticGanoderma Lucidum Spore Oilto Achieve Enhanced Protection against Radiation‐Induced Heart Disease

“…As is reported, mitochondria are vital in producing energy to support activities for living cells . However, serious depletion of mitochondrial membrane potential (Δ Ψ m ) indicates mitochondrial dysfunction, even causing cell death . Therefore, flow cytometric analysis by JC‐1 probe (a mitochondrial potential sensor) was conducted to examine the status of mitochondria in H9C2 cells exposed to X‐rays after different protection strategies.…”

Iminoboronate Backbone‐Based Hyperbranched Polymeric Micelles with Fenton‐Like Enhanced ROS Response

“…[ 15,16 ] The differentiated ROS level in different regions inspires the development of ROS‐responsive micelles for targeted drug delivery. [ 17–19 ] Motifs such as thioether, thioketal, ferrocene, tellurium, selenium, and boronic ester are introduced to the structures of the polymers to endow the self‐assembled micelles with ROS‐responsiveness. [ 20–24 ] However, current designs always allow the micelles to exhibit responsive drug delivery at relatively high concentrations of ROS, which is the main obstacle to limit their further uses.…”

“…Cancer tissues are usually featured with mild acidic conditions and high ROS levels due to the fast metabolism‐induced overproduction of metabolic products. [ 17–29 ] In addition, the concentration of Cu(II) ions in cancer cells is 2–3 times higher than that within normal cells (0.98 µg mL −1 ), while the concentrations of Zn(II), Fe(III), and Se(II) are significantly lower in cancer tissues. [ 30 ] It should be noted that a Fenton‐like reaction may occur for the polyphenols and Cu(II) complexed system to quickly generate a variety of reactive oxygen species.…”

6‐Triphenylphosphinehexanoic Acid Conjugated Near‐Infrared Persistent Luminescence Nanoprobe for Autofluorescence‐Free Targeted Imaging of Mitochondria in Cancer Cells

“…To meet the unmet needs for the purpose mentioned above, a diverse array of mitochondria‐targeting luminescent probes have been developed, including organic dyes, fluorescent peptide, fluorescent‐label DNA, semiconductor nanocrystals, and polymer fluorescent platforms . Despite these luminescent probes have been successfully applied for the mitochondria imaging depending on their own specific advantages, some drawbacks could not be neglected, especially the inevitable tissue autofluorescence interference.…”

“…Moreover, organic dyes usually suffer from photobleaching. Polymer fluorescent platforms can be flexibly designed for optimal optical properties, but usually require complicated synthesis process . Thus, it is still an unprecedented challenge to develop photostable probes for autofluorescence free targeted imaging of mitochondria with high specificity and biocompatibility.…”